The Molecular Genetics Program conducts fundamental research on the etiology, progression, prevention, detection, and treatment of cancer with the goal of using the Cancer Center to translate these fundamental discoveries to our patients and population resources. The scientific focus of this group of 24 faculty members is on DMA damage, chromosomal translocation sites, chromosomal fragile sites, DMA repair mechanisms and proteins, DNA replication mechanisms and proteins, familial cancer gene identification, and mammalian cancer models. The 24 member group from 10 academic departments in three schools has Minisymposia, Cancer Center Strategy Sessions, weekly data presentation meetings, and annual poster sessions in addition to the weekly Cancer Center Grand Rounds, as forums for interaction. For purposes of developing program projects and other grants, the Molecular Genetics Program is subdivided into three focus groups: DNA Repair, DNA Replication, and Cancer Genetic Models. Many major cancer research discoveries have been made in the previous funding interval. New DNA repair proteins have been identified, and these are being explored as possible chemotherapy drug targets. The basis for the most common chromosomal translocation in human cancer was defined as being due to a triplex DNA structure. An entire class of DNA polymerases was defined. Collaborations within the Program have shown that these polymerases participate in the major pathway of double-strand break repair. A program project on polymerase active sites was secured and will permit rationale design of polymerase inhibitors for cancer chemotherapy. Marked progress has also been made in understanding the persistence of hepatitis viruses, which are important in causing hepatocellular carcinoma. Other Program members are collaborating to study cancer genetic models of prostate and ovarian cancers and have developed a conditional knockout mouse, widely regarded as being the best currently available for prostate cancer. Genetic linkage analysis of prostate cancer families is underway, and is integrated into an international consortium. Hence, both scientific collaborations and cancer research discoveries are facilitated by the existence of the Molecular Genetics Program. Of the 212 publications over the last five years, 10.4% were intraprogrammatic collaborations and 10.4% were interprogrammatic collaborations. The Program is supported by $6.3 million in direct peer-reviewed support per year of which $2.1 million is from the NCI.